Calcium phosphates (CaP), such as hydroxyapatite, tricalcium phosphates and other soluble calcium phosphates (brushites) and others, have found many biomedical applications over the years. Hydroxyapatite and other calcium phosphate implants exhibit good tissue compatibility and help the formation of new bone without forming any fibrous tissues because their chemical compositions are similar to that of bone material. Recently, Varghese et al., using a mineralized synthetic matrix mimicking a CaP rich bone microenvironment, demonstrated the beneficial role of CaP biomaterials in bone repair and the role of calcium and phosphate ions in bone physiology and remineralization. In bone tissue engineering, calcium phosphates have been applied as filling materials for bone defects and augmentation, artificial bone graft material, and in prosthesis revision surgery. Its high surface area leads to excellent osteoconductivity and resorbability providing fast bone in-growth. In dentistry, dentifrices and varnishes containing calcium ions, phosphate ions and fluoride ions are being used for the remineralization of dentinal tissues. Calcium containing cements find use as structural supports in orthopedic and dental applications. In a recent study, Schumacher et al. developed biologically active restorative materials that may stimulate the repair of tooth structure through the release of cavity-fighting components including calcium and phosphate. They disclosed the use of amorphous calcium phosphate (ACP) as a bioactive filler encapsulated in a polymer binder. Calcium and phosphate ions released from ACP composites, especially in response to changes in the oral environment caused by bacterial plaque or acidic foods, can be deposited into the tooth structures as an apatite mineral, which is similar to the hydroxyapatite found naturally in teeth. The ACP has the properties of both a preventive and restorative material. This encourages its use in dental cements, sealants, composites, and, more recently, orthodontic adhesives. ACP-filled composite resins have been shown to recover 71% of the lost mineral content of decalcified teeth. Though ACP has been used in some dental applications, its use in dental restorative materials is very limited due to its stability. In contact with water, ACP turns into hydroxyapatites.
There has been a lot of research on the development of calcium phosphates and hydroxyapatites for various biomedical applications. A calcium phosphate useful in biomedical applications should possess at least the following properties: (1) it should be chemically biocompatible like hydroxyapatite; (2) it should be in soluble form to permit resorption so that the patient's own bone can replace the foreign hydroxyapatite; and (3) it should be able to mix into a matrix formulation without losing its chemical integrity, its bioactivity and its ability to release beneficial ions, such as calcium and phosphate.
A number of researchers have reported on the production of crystalline hydroxyapatites. These involve either solution precipitation followed by sintering at very high temperatures such as (800-1200° C.) (LeGeros, Calcium Phosphates in Oral Biology, Karger Pub, N.Y., 1991) or solid state acid base reaction of primarily crystalline calcium phosphates. These methods generate highly crystalline phases with limited solubility.
The formation of calcium phosphate minerals by the reaction of phosphoric acid and calcium source in the presence of a base and hydroxyapatite crystals has been reported by Contstantz in U.S. Pat. No. 4,880,610. He also studied the use of powdered acid salts to improve the workability in U.S. Pat. No. 5,053,212, and the use of a mixture of calcium phosphate salts and carbonates in sodium phosphate solution to generate a calcium phosphate material with substantially greater crystallinity than in naturally occurring bone.
Palmer et al. in U.S. Pat. No. 4,849,193 reported the formation of crystalline hydroxyapatite powder by reacting an acidic calcium phosphate solution with a calcium hydroxide solution to generate an amorphous hydroxyapatite powder. These amorphous powders were then dried and sintered at 700° C.-1100° C. to generate high crystalline hydroxyapatite. Recently, Arsad et al. reported the synthesis and characterization of hydroxyapatites formed by the reaction of calcium chloride and a phosphate source. More recently other wet methods have been developed for the synthesis of nanosized hydroxyapatite crystals from calcium nitrate and sodium phosphate salts.
Though the preparation of crystalline calcium phosphate and its use in dental cements has been reported by Brown et al., Tung et al. were the first to disclose the use and application of standard amorphous calcium phosphate for the remineralization of teeth. The amorphous calcium phosphates, incorporated in the chewing gum, released soluble calcium and phosphate ions and formed crystalline hydroxyapatite in oral conditions. The effective application of ACP is limited in restorative or regenerative dentistry and is limited due to its instability in and incompatibility with monomers containing acidic functional groups.
Various researchers have attempted to stabilize and protect calcium phosphate particles with polyethylene glycol and sugar alcohols. These protected calcium phosphates have efficiently released calcium and phosphate ions and helped in the remineralization of dentin tooth surfaces. Thermodynamically stabilized calcium phosphate clusters, using phosphoprotein molecules at a pH in the range of 6-7.2 have been reported by Holt et al. in U.S. Pat. No. 7,060,472. Stabilization using phosphopeptides at pH above 7 is reported by Reynolds et al. in U.S. Pat. No. 7,312,193. Pugh et al. in U.S. Pat. No. 6,585,992 reported a synthetic biomaterial compound based on stabilized calcium phosphate and, more particularly, the molecular, structural and physical characterization of calcium phosphate compounds stabilized with boron and silicon. Amsden et al. in U.S. Pat. No. 8,529,933 reported the synthesis of biphasic calcium phosphate cement for drug delivery that incorporated biopolymer carriers for the site-specific introduction of natural or synthetic compounds to influence bone repair and/or patient recovery. Pugh et al. in U.S. Pat. Appl. No. 2007/0184035 described the artificial stabilization of calcium phosphate phases developed by the conversion of a hydroxyapatite substance into insolubilized and stabilized tricalcium phosphate. They also described applications for this material in medical diagnostics for the assessment of abnormal bone cell activity and for medical therapeutics, including bone and dental tissue replacement and repairs and for ex vivo bone graft tissue engineering. Reynolds et. al. in U.S. Pat. Appl. No. 2014/0079650 disclosed the synthesis of stabilized calcium phosphate synthesized below a pH of 7 and its applications in dental remineralization including in formulations such as mouth wash and chewing gum. Rusin et al. in U.S. Pat. No. 8,790,707 described the surface modification of calcium phosphate particles with a sugar alcohol and/or at least one glycerophosphoric acid compound. They also described oral care compositions comprising surface treated calcium phosphate particles. Yang et al. in U.S. Pat. No. 8,263,048 described calcium phosphate particles surface treated with sugar alcohols and their application in oral formulation.
Jia in U.S. Pat. No. 6,270,562 disclosed a dental composition with a glass filler material having bonded surface modifying particles, including fluoro-alumino silicate glasses and a composition with resins, glass fillers and treated glass fillers. Other concepts disclosed include the preparation of amorphous calcium phosphate particles precipitated on zirconium, titanium and silica particles and compositions including amorphous calcium phosphate supported with filler particles and resins. Though these methods would generate amorphous calcium phosphate particles, their stability still has not been improved and their application in combination with acid containing adhesive monomers is limited.
Another drawback of calcium phosphate cements is their low mechanical properties. Hydroxyapatite as a bulk solid does not have the necessary mechanical properties, such as strength or stiffness, to be used in load bearing applications. While much has been learned about the structure and growth of bone tissue due to modern microscopy, no reliable method of synthesizing this structure has been developed.
Experience with calcium-based implants for the replacement of skeletal tissue has also existed for many years. Most of these implants have been in the form of prefabricated, sintered hydroxyapatite in either granule or block forms. These preparations have several drawbacks, including a limited ability to conform to skeletal defects, particularly in the case of blocks, inadequate structural integrity of granules (which do not bond together), and difficulty in modeling the implant to the shape of missing skeletal tissue with both blocks and granules. The block form of hydroxyapatite provides structural support, but among other complications, must be held in place by mechanical means, which greatly limits its use and its cosmetic results. It is also very difficult to saw a shape such that it fits the patient's individual defect. The granular form produces cosmetically better results, but has a very limited structural stability and is difficult to contain during and after a surgical procedure. In general, all of these products are ceramics, produced by high temperature sintering, and are not individually crystalline, but rather have their crystal boundaries fused together. These ceramic-type materials are in general functionally biologically non-absorbable (having an absorption rate generally not exceeding on the order of 1% per year). For example, both apatite and brushite cements are commercially available, but their usefulness in the construction of bone defects and their behavior in the bone defect are quite different due to their difference in the resorption. Brushite cements are resorbed much faster compared to apatite cements. The difference is caused by the compositional difference in the final products. Therefore, the final product of apatite cement is apatite and the final product of brushite cement is brushite
The patent literature does, however, describe at least one class of calcium phosphate compositions which are precursors for the formation of hydroxyapatite. These compositions offer good remineralization potential as slurries and are biologically compatible, self-setting (self-hardening), and substantially resorbable (biodegradable) with bone replacement as cements when implanted in contact with living bone tissue. For example, U.S. Pat. Nos. Re. 33,221 and Re. 33,161 to Brown and Chow teach preparation of calcium phosphate remineralization compositions and finely crystalline, non-ceramic, gradually resorbable hydroxyapatite cement based on the same calcium phosphate composition. However, these cements lack the mechanical strength required for medical implants where high load strength is required. Somewhat similar, and in certain instances potentially identical products, are described in U.S. Pat. Nos. 5,053,212, 4,880,610, 5,129,905, 5,047,031, and 5,034,059 to Constantz and others, although the use of non-traditional chemical terminology in the latter patents makes interpretation of them and comparison of them with the prior work of Brown and Chow difficult.